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Dual Targeting of ErbB2 and MUC1 in Breast Cancer Using Chimeric Antigen Receptors Engineered to Provide Complementary Signaling

Wilkie, Scott ; van Schalkwyk, May C. I. ; Hobbs, Steve ; Davies, David M. ; van der Stegen, Sjoukje J. C. ; Pereira, Ana C. Parente ; Burbridge, Sophie E. ; Box, Carol ; Eccles, Suzanne A. ; Maher, John

Journal of clinical immunology, 2012-10, Vol.32 (5), p.1059-1070 [Periódico revisado por pares]

Boston: Springer US

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Título:
Dual Targeting of ErbB2 and MUC1 in Breast Cancer Using Chimeric Antigen Receptors Engineered to Provide Complementary Signaling
Autor: Wilkie, Scott ; van Schalkwyk, May C. I. ; Hobbs, Steve ; Davies, David M. ; van der Stegen, Sjoukje J. C. ; Pereira, Ana C. Parente ; Burbridge, Sophie E. ; Box, Carol ; Eccles, Suzanne A. ; Maher, John
Assuntos: Adaptor Proteins, Signal Transducing - immunology ; Biomedical and Life Sciences ; Biomedicine ; Breast cancer ; Breast Neoplasms - immunology ; CD28 antigen ; Cell Line, Tumor ; Cell Proliferation ; Cells, Cultured ; Cytotoxicity ; ErbB-2 protein ; Female ; Humans ; Immunology ; Immunotherapy ; Immunotherapy, Adoptive ; Infectious Diseases ; Interferon-gamma - immunology ; Interleukin 2 ; Interleukin-2 - immunology ; Internal Medicine ; Lymphocytes T ; Medical Microbiology ; Microenvironments ; Mucin-1 - immunology ; Niches ; Receptors, Antigen, T-Cell - immunology ; Signal Transduction - immunology ; T-Lymphocytes - immunology ; Transgenes ; Tumor cells
É parte de: Journal of clinical immunology, 2012-10, Vol.32 (5), p.1059-1070
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Descrição: Purpose Chimeric antigen receptor (CAR) engineered T-cells occupy an increasing niche in cancer immunotherapy. In this context, CAR-mediated CD3ζ signaling is sufficient to elicit cytotoxicity and interferon-γ production while the additional provision of CD28-mediated signal 2 promotes T-cell proliferation and interleukin (IL)-2 production. This compartmentalisation of signaling opens the possibility that complementary CARs could be used to focus T-cell activation within the tumor microenvironment. Methods Here, we have tested this principle by co-expressing an ErbB2- and MUC1-specific CAR that signal using CD3ζ and CD28 respectively. Stoichiometric co-expression of transgenes was achieved using the SFG retroviral vector containing an intervening Thosea asigna peptide. Results We found that “dual-targeted” T-cells kill ErbB2 + tumor cells efficiently and proliferate in a manner that requires co-expression of MUC1 and ErbB2 by target cells. Notably, however, IL-2 production was modest when compared to control CAR-engineered T-cells in which signaling is delivered by a fused CD28 + CD3ζ endodomain. Conclusions These findings demonstrate the principle that dual targeting may be achieved using genetically targeted T-cells and pave the way for testing of this strategy in vivo.
Editor: Boston: Springer US
Idioma: Inglês

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Dual Targeting of ErbB2 and MUC1 in Breast Cancer Using Chimeric Antigen Receptors Engineered to Provide Complementary Signaling

Wilkie, Scott ; van Schalkwyk, May C. I. ; Hobbs, Steve ; Davies, David M. ; van der Stegen, Sjoukje J. C. ; Pereira, Ana C. Parente ; Burbridge, Sophie E. ; Box, Carol ; Eccles, Suzanne A. ; Maher, John

Boston: Springer US

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